Objectives The main objective of this work is define interactions of molecular chaperones which can serve as targets for AIDS or cancer therapies ABSTRACT:Our data indicate that CsA analogs inhibit HIV/SIV replication by a mechanism that does not involve the calcineurin-mediated immunosuppression pathway. We have also found that RNA encapsidation is not deficient in virions produced by CsA treated cells. The infectivity of virions from cultures treated with virus-inhibitory compounds (such as, e.g., [MeLeu(3-OH)1, MeAla4,6]-CsA) is approximately one hundred-fold lower than that of HIV from control cultures. The capacity of the compounds to decrease HIV infectivity requires their ability to bind and inhibit a molecular chaperone known as cyclophylin A (CyP A), because [MeBm2t1]-CsA, which has greatly reduced binding to and inhibition of CyP A, does not affect the infectivity of virions. The involvement of the CyP family of PPIases in HIV replication appears to be specific, because the inhibition of the FKBPs with rapamycin does not decrease HIV replication or virion infectivity. Presentation of cytosolic peptides in the context of major histocompatibility complex (MHC) class I antigen is crucial for immune recognition of virus-infected and malignant cells. To address the involvement of molecular chaperones in the presentation of cytosolic peptides, we have utilized B16 melanoma cells. These tumor cells are resistant to lysis by MHC class I-restricted cytotoxic T lymphocytes (CTL), due to a very low level of surface MHC expression. We have found that stably transfected clones of B16 expressing a heterologous chaperonin (GroEL) homolog exhibit significantly increased levels of MHC class I antigens on their surface, and are effectively lysed by alloreactive CTL. Moreover, these MHC molecules can form functional MHC-peptide complexes which are recognized by virus-specific CTL. Together, these results indicate that the suitable expression of a molecular chaperone can overcome a defect in MHC class I expression and antigen presentation. Keywords HIV, SIV, Cyp A, MHC, melanoma